Top 10 HIV/AIDS-Related Clinical Developments of 2011

5. No Go Isentress+Prezista/Norvir

Cowboys and cowgirls, you know who you are. You are the early adapters; the ones who see a presentation on a 50-patient, single-armed study from France of a novel ART combo and can't wait to try it in clinic when you get back home. You extrapolate and eschew evidence-based-minded colleagues as stodgy. Often, you are considered a thought leader. Usually, the data catches up and vindicates your prescience. Except sometimes it does not.

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A year or so ago, the NRTI-sparing regimens had a bit of a renaissance with the advent of the integrase inhibitor Isentress (raltegravir). The bold among us started to use imaginative pairings of Isentress with boosted protease inhibitors in an effort to relieve us of the NRTIs and provide an attractive option for those failing Atripla (efavirenz/tenofovir/FTC). The inklings were there. In ACTG study A5142, the NRTI-sparing regimen of Kaletra (lopinavir/ritonavir) plus Sustiva produced a virologic response that was no different than two NRTIs plus Sustiva among treatment-naive patients.11 The major limitation of that two-drug regimen was tolerability, not efficacy.

So, all we needed to do was a study to prove us right, and A5262 was to be it. In this single-arm study, 112 ART-naive patients were treated with Prezista (darunavir, TMC114) plus Norvir (800 mg/100 mg daily) plus Isentress (400 mg twice daily).12 The single-arm design was intended as an efficient and quick way to study this novel combination. Without a comparator arm, the study was designed to look at response relative to the results of other treatment-naive studies. The acceptable virologic failure rate was estimated using the week 24 virologic failure rates of the Sustiva plus two-NRTI arm of A5142 (22 percent); the Sustiva plus two-NRTI arm of ACTG A5095 (17 percent); and the Truvada plus Isentress arm in several trials (10 percent to 15 percent). It was pre-specified that the study regimen would be considered satisfactory if the upper bound of the confidence interval for cumulative virologic failure at week 24 was less than 35 percent.

When the dust settled, 17 (16 percent) of the participants experienced virologic failure (95% CI 10-24) by week 24 and 26 percent (95% CI 19-36) by week 48 in an intent-to-treat analysis. Eleven participants had failed to suppress viremia and six rebounded. An additional 11 participants experienced virologic failure after week 24, for a total of 28 virologic failures during the study. In the intent-to-treat analysis (missing and off study without virologic failure were ignored), the viral load was less than 50 copies/mL in 79 percent (95% CI 70-86) of participants at week 24 and less than 50 copies/mL in 71 percent (95% CI 61-79) of participants at week 48. Interestingly, 21 of the 28 who failed had baseline viral load levels of greater than 100,000 copies/mL. After adjusting for age and sex, virologic failure was associated with a baseline viral load of more than 100,000 copies/mL and a lower CD4+ cell count. Five participants had integrase mutations during virologic failure and all had a baseline viral load of more than 100,000 copies/mL. No new protease inhibitor resistance was detected among those failing. Overall, the regimen was well tolerated.

The Bottom Line

The combination of Prezista+Norvir+Isentress did not bomb, but the results were nonetheless disappointing. Using a modified intent-to-treat analysis where missing and off treatment were considered to be failure, only 61 percent of participants had a viral load below 50 copies/mL at week 48 -- a response rate that was much lower than that seen with standard initial regimens and the A5142 NRTI-sparing combination.

The reason for the lackluster response of the study treatment is unclear. Self-reported adherence was not different between those who did and did not experience virologic failure. However, a lower plasma level of Prezista or Isentress was associated with failure, possibly indicating unreported suboptimal adherence. Further, in another study, the PROGRESS trial, Isentress+Kaletra was found to provide similar virologic responses as Kaletra+Truvada. A potentially important difference between that and the ACTG study was an overall lower baseline viral load in the PROGRESS trial.13

It is the finding that a high baseline viral load was strongly associated with virologic failure that suggests an issue with potency. It is never a good sign when a regimen falls flat among those with higher viral loads. Some have speculated that effective ART regimens require a drug active prior to the integration step of the viral life cycle, thus the better success of an NNRTI plus protease inhibitor combination. Regardless of the cause for the higher-than-expected rate of virologic failure, this regimen should be used cautiously, especially in those with higher viral loads.

The pull to go beyond the evidence is strong in the field of HIV management. Patients burn through regimens faster than clinical trials can provide data to guide the next steps. With over 25 drugs on our palette, we concoct mixes that should work based on what we know and believe. This is what makes HIV care exciting and, to some extent, creative. The story of A5262 shows us, though, that we can be wrong and that faith may be unwarranted. Sometimes, even the best cowboys and cowgirls lose, only to fight another day.

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